Controlled release pharmaceutical tablets containing an active principle of low water solubility

ABSTRACT

It is described a new method for the preparation of pharmaceutical tablets carrying poorly soluble in water principle; this method allows to obtain tablets with fast and/or slow release of the active principle. The peculiar feature is the fact that the poorly soluble in water active principle (es: nifedipine) is treated with a surfactant, during the granulation phase or whatever during the preparation process; the obtained product, subjected to a compression, produces pharmaceutical tablets which show high bioavailability of the carried active principle. This procedure can be used to prepare polymeric matrixes (with modified release), formed by tablets with one or more layers. The procedure of manufacture and the characteristics of the new finished tablet are described.

FIELD OF THE INVENTION AND STATE OF THE ART

Biological active agents poorly soluble in water or in biological fluidshave always represented remarkable problems of bioavailability when theyare administered in pharmaceutical formulations for oral use.

This problem happens both in the case of preparation of fast releasetablets and, mostly, in the case of tablets and/or whatever oftherapeutic systems from which the active principle has to be releasedin an extended interval of time.

In fact, in the case of so-called “retard” tablets, the very lowsolubility of the drug produces a very changeable release speed of theactive principle from the pharmaceutical formulation and, asconsequence, a changeable and wrong absorption and, therefore,therapeutical effect.

Practically the dissolution speed of the active principle results as therestrictive factor of the absorption process and the followedtherapeutic activity.

Many attempts have been carried out to modify the parameters whichinfluence the dissolution speed of a biological active and poorlysoluble agent.

The employment of micronized active agents, which show so widesuperficial area, results widely utilized and well known by the expertof the art.

In fact, the process of dissolution of an active agent is regulated ofthe Noyes and Withney law which is usually expressed in the followingform: $\frac{c}{t} = \frac{{DS}\left( {{Cs} - C} \right)}{h}$

wherein

dc/dt=dissolution speed; it is the quantity of agent that dissolves inthe unit of time

D=diffusion coefficient of the substance (depending from the molecularweight, from the viscosity of the medium, from the temperature, etc.)

h=thickness of the diffusion layer

S=total superficial area exposed to the medium of dissolution

Cs=concentration of the agent in the diffusion layer

C=concentration of the drug in solution in mass.

Procedures of micronization have been used to increase the dissolutionspeed of a lot of active principles like, for example: chloramphenicolpalmitate, terfenadine, nitrofurantoine, naftazone, griseofulvine, evenif, in this last case, an increase of the dissolution speed gives agreat increase both of the activity but mostly of the toxicity of theproduct.

Also in the case of nifedipine, a drug widely used in the treatment ofhypertension, it is known that a rapid effect of the drug can beobtained by using the micronized product, while by using the activeprinciple in a greater granulometry or more precisely with a superficialarea lower than 5 m²/g it is obtained a retard in the dissolution speedand therefore a slower absorption speed and, consequently, a retardedtherapeutical effect. This last procedure to obtain slow releasepharmaceutical formulations has been claimed in German patents 2,209,526and DE A1 3,033,991 even if the active agent with a precise granulometryand/or with a superficial area under the limits described in the quotedpatent is particularly complex and not easily standardizable to obtain.

Different methods have been carried out to increase the dissolutionspeed of poorly soluble active agents like, for example, thetransformation of the active substances from a crystalline to anamorphous state which represents, usually, an increase of the solubilityand so of the dissolution speed too, for example the1-acetoxy-ethyl-cefuroxime (axetylcefuroxime) (v. Gouda M. W. et al:Drug Develop. & Ind: Pharm. 3, 273, 1977).

To obtain similar results clathrates or inclusion complexes withpolymers like polyvinylpyrrolidone, polyoxyethylenglycol,polyvinylalcohols, celluloses and derivatives have been prepared and inparticular the complexes with cyclodextrins have provoked a lot ofinterest, even if it has to be underlined that these modificationsinvolve a great increase of weight of the pharmaceutical formulationbecause at least a ratio of 1:1 molar between the drug and the polymeris usually utilized.

A wide series of possibilities to increase the dissolution speed ofpoorly active principles is described in the test “Technique ofsolubilization of drugs” of S. H. Yalkowsky-M. Dekker New York 1985.

A different technique to increase the dissolution speed of not verysoluble active agent is claimed in the Italian patent no 1.188.165 (seeapplication no 20474 A/85) and in the Italian patent no 1.246.188 and inthe U.S. Pat. No. 5,476,654 in which it is used a procedure to load thepoorly soluble drug on a support formed by hydrophylic swollen polymersor through a co-mixing and/or co-grinding process.

Nevertheless, all these methods allow to obtain an increase of thedissolution speed of an active principle but they don't guarantee abetter bioavailability of the same, in particular, when this poorlysoluble active principle, is carried out in a pharmaceutical formulationfor oral use.

Like above mentioned, an increase of the dissolution speed of a poorlysoluble drug is necessary for the preparation of fast-release tablets,but mostly for modified-release tablets, in order to allow that theabsorption of the drug is not limited from the speed of itssolubilization.

In the particular field of the controlled or modified release, thesystems able to release the active principle at constant speed duringtime, namely systems that are usually defined with zero-releasekinetics, are great important.

In fact, for example, in the case of hydrophilic matrixes, which formthe class of the most utilized and diffused pharmaceutical formulations,the release of the drug shows at the beginning the fast release of adose fraction (“burst effect”), phenomenon which has to be avoidedbecause it can determine the outbreak of toxic effects linked toexcessive absorption.

To avoid the “burst effect” different solutions have been proposed andadopted like to save a fraction of the matrix surface with a waterprooflayer, at least for a determined interval of time, like described in theU.S. Pat. No. 4,839,177 and U.S. Pat. No. 5,422,123.

A different solution to the problem of the “burst effect” is thesuggestion to add, in the formulation of the hydrophilic matrix,ionizable, pharmaceutically acceptable, compounds.

This last solution is reported in the U.S. Pat. No. 5,419,917 in whichit is described that the employment of polar substances in anhydrophilic matrix shows a great reduction of the dissolution speed ofthe active principle carried in the hydrophylic matrix.

DESCRIPTION OF THE INVENTION

Now we have unexpectedly found, and it is the object of the presentindustrial patent, that, the use of particular concentrations ofsurface-active agents in a hydrophilic matrix, allow to obtain anincrease of the dissolution speed of a poorly soluble drug and, in thisway, also an improvement of the absorption and bioavailability of theactive principle carried in this matrix.

These systems of matrix release, composed by pharmaceutical tablets ofone or more layers, one of which contains the active principle, can beproduced by using precise productive and high industrial reproducibletechnologies. Moreover, we have, unexpectedly found that these systemsdo not determine “burst effect” and especially, they allow to eliminatethe variability of the absorption caused by differences in thegranulometry of the poorly soluble active principle.

In this way we have carried out and experimentally proved a newtherapeutic system, with modified and controlled release, that solvesthe problem of the “burst effect” bound to the matrix systems. Thissystem shows innovative advantages of safety and therapeutic efficacy,because the release of the active principle happens in a complete andreproducible way and the absorption results effective and high, like itis showed by the data relative to the plasma concentrations (C_(max)),obtained after the administration to the healthy volunteer, as it willbe reported in the examples of the present patent.

Object of the present invention is a tablet of one or more layers one ofwhich, at least, carries the active principle while the other one, orthe others layers, have mostly the function of barrier with the purposeto modulate, for a determinable period of time, the release of thecarried drug from the layer including the drug (For the geometry of thesystems with more layers it refers back to what described in the aboveU.S. Pat. No. 5,422,123).

One of the characteristics of the tablet of the invention consists inthe fact that in the preparation of the treated layer (or nucleus),beyond the active principle and a surface-active agent, also polymericsubstances are utilized able to modulate (to slow down and/or to speedup) the release of the active principle.

As poorly very soluble in water substances (which show a solubility at20° C. less then 50 mg/ml) many drugs can be used, including, in orderto illustrate and not to limit: nifedipine, ricardipina, nitrendipine,nimodipine, niludipine, nilvadipine, nisoldipine, fenofibrate,naftazone, terfenadine.

These poorly soluble in water active substances are included in thetreated layer (or nucleous) in a percentage from 9 to 80% of the weight,preferably from 20 to 60%.

The system is characterized by the fact that in the preparation of saidnucleus or layer which containing the active principle, surfactantsubstances or substances with hydrophilic characteristics of acceptablepharmaceutical type, are used, selected from the group consisting of:

anionic surfactants

cationic surfactants

non-ionic surfactants

polyoxyethylenglycols (PEG) with molecular weight from 200 to 200,000

copolymers to polyoxyethylenic/polyoxypropylenic blocks (Poloxamer)

N, N′, N″, N″′ tetra-(polyoxyethylen)(polyoxypropylen)diaminoethylene(Tetronic, Poloxamine)

dimethylpolysiloxane (Simethicone).

In order to illustrate and not to limit, the substances with surfactantproperties, the following ones are reported: sodium lauryl sulphate,aluminium monostereate, sodium cetostearyl sulphate, magnesium andammonium lauryl stearate, mono-, di-, triethanolamine laurylstearate,glycerylmonostearate, glycerylmonoleate, lauromacrogols (polyethoxylatedlaurylic alcohol), polysorbates of different pharmaceutical degree (theyusually contain from 20 to 120 mols of C₂H₄O), esters of sorbitane withfatty acids, alkyldimethyl-(phenylmethyl) ammonium hydrochloride,cholesterol, bile acids and relative salts or esters or derivatives,lecithines, nonoxynoles or macrogolnonylphenylethers (polyethoxylatednonylphenols).

Said surfactants can be added to the active agent either with simplemixing or, in the case of a previously prepared granulated, using othercomponents, too, like coadjuvants. These surfactants can be added, forexample, to the binder solution, like it is well known in the prior art.

These hydrophyle or surfactants substances are included in thepharmaceutical formulation in a percentage from 1% to 40% of the weightof the treated layer, preferably from 2% to 30%.

As polymeric substances in the preparation of said layer (or nucleus)can be used, for example, reticulated polyvinylpyrrolidone,hydroxypropylmethylcellulose, reticulated sodiumcarboxymethyl-cellulose, carboxymethylstarch, potassiummethacrylate-divinylbenzene copolymer, polyvinylalcohols,hydroxypropylcellulose at molecular weight from 2,000 to 4,000,000,carboxyvinylpolymers, glucanes, scleroglucanes, mannanes,galattomannanes, gellanes, xanthanes, alginic acid and derivatives,polyanhydrydes, polyaminoacids, poly-(methyl vinyl ethers/maleicanhydryde), carboxymethylcellulose and derivatives, ethylcellulose,methylcellulose and in general cellulosic derivatives, starchs, starchderivatives, alfa, beta, gamma cyclodextrins and in general dextrinderivatives.

These polymeric substances form from 3% to 90% of the weight of thelayer (or nucleous), but preferably from 5% to 50%.

For all above polymers, many types characterized by different chemicaland physical properties, solubility and gelling are present in themarket, in particular, regarding the hydroxypropylmethylcellulose manytypes with different molecular weight (from 1,000 to 4,000,000) anddifferent level of substitution can be used. Said types ofhydroxypropylmethylcellulose show different characteristics because theyare usually erodible and able to produce gels, by the way of theviscosity and the degree of substitution (D.S.) shown in the polymericchain.

At least, usually in pharmaceutical technique excipients like: mannitol,lactose, sorbitol, xylitol, talc, stearic acid, sodium benzoate,magnesium stearate, colloidal silica and others like glycerylmonostearate, hydrogenated ricine oil, waxes, mono, bi-, trisubstitutedglycerides, glycerilpalmitostearate, glyceryl behenate, cetylic alcoholcan be used.

When it is desired to allow the penetration of water and/or aqueousfluids in the layer or nucleous, hydrophilic diluents are included likemannitol, lactose, starchs of different source, sorbitol, xylitol, or tocarry in the formulation moistening substances and/or in generalfavouring the penetration of water in the compact. When it is desired toslow down the penetration of water and/or aqueous fluid in the treatedlayer or nucleus, hydropholic diluents are included like glycerylmonostearate, hydrogenated castor oil, waxes, mono-bi-trisubstitutedglycerides. Moreover substances can be used like diluents, binders,lubricants, buffers, not adhesives, glydants, plasticizers and othersubstances, able to give to this layer the wanted characteristics likein the examples afterwards reported.

The pharmaceutical tablets of the invention have the advantage torelease the carried active principle in a programmed way.

The system, in the simplest achievement, is a tablet with one or morelayer at least one of which contains the active agent.

The formulation of the “barrier” layers includes polymeric substancesand coadjuvants and plasticizer substances; when this tablet is of threelayers called “barrier”, they either can be similar one each other bothfor the composition and the thickness or they can be different.

The polymeric substances carried out in the different “barrier layers”are reported in the previous description of the nucleus or treatedlayer.

These polymeric substances occur in a percentage from 5% to 90% of thetotal weight of this layer and preferably from 50% to 90%.

Similarly, for the preparation of said layers, the coadjuvant substancesprevious described can be utilized.

It is possible to produce these systems with one or more layers, byusing installations and equipments of widely consolidate use inpharmaceutical field and able to assure a safe and precise realizationof the system with not much expensive cost (es: Elisabeth Hata).

Over these finished tablets, further polymeric coating material can beapplied in order to cover the system, and to allow a protection for thetablet or a protection against light for the photosensitive activeprinciple carried by this tablet or it can be a further slowing down inthe beginning phase of the release.

Said coating can be soluble in an acid medium or permeable or it can begastric resistant and enterosoluble, in order to allow the activation ofthe system only after the arrival of the tablet in the intestinal tract.

For the coating of these systems, the classical materials for the sugarcoating or either natural and/or synthetic rubbers, like shellac,sandarac rubber, etc. or lypophylic material like natural waxes (whiteor yellow) or semi-synthetic derivatives can be used.

Moreover film forming polymeric materials can be used, like: cellulosederivatives (hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and their derivatives), acrylic and methacryliccopolymers of different molecular weight. In order to obtain the gastricresistance, many materials can be employed, like: zein, celluloseacetophthalate, cellulose acetopropionate, cellulose trimellitate,polyvinyl acetate phthalate, acrylic and methacrylic polymers andcopolymers of different molecular weight and with a solubility thatdepends from different values of pH.

Said materials can be applied on the finished pharmaceutical formulation(tablet with one or more layers) through the classic method of filmcoating by using solutions in organic solvents or aqueous dispersionsand working with a basin for atomization or in fluidized bed.

Said both gastric-soluble or gastric-resistant and entero-solublematerials can be employed in association with other retardant polymersand in association with other substances which have the function ofplasticizers like: triethylcitrate, diethylphthalate, benzylbenzoate,dibutylsebacate, sorbitol, propylenglycol, diacetin, triacetin,dibutylphthalate, tributylacetate, castor oil, cetyl alcohol,cetylstearyl alcohol, fatty acids, polyoxyethylenglycols, usuallyselected from the group having a molecular weight from 200 to 200,000.

The coating layer can be applied, too, through the method of dry coatingby using the above described materials, possibly previously granulated,like every expert of the field well knows.

The examples and the obtained results in the described experimentaltrials put better in evidence the characteristics and thefunctionalities of the new system. In any case, the innovation of therealization is characterized by the fact that the claimed therapeuticsystem can be obtained by using the usually productive technologies,that is the system is transferable in an industrial process.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the drug release in percent on the starting whole content,during the time, for the tablets according to Example 1, 2, and 3.

FIG. 2 shows a drug release in percent on the starting whole content,during the time, for the tablets according to Example 4, 5, and 6.

EXAMPLE 1

Preparation of a series of (5,000) tablets containing nifedipine 60 mgas active principle.

1-a-Composition of the first layer:

% weight Nifedipine (0.5 m²/g) 60.0 mg 41.66 Lactose monohydrate (USPgrade) 40.0 mg 27.77 Hydroxypropylmethylcellulose 20.0 mg 13.88(Methocel K100 M, Colorcon, Orpington, UK) Polyvinylpyrrolidone(Plasdone K29-32, 10.0 mg 6.94 I.S.P., Wayne, NY, USA) Sodiumlaurylsulphate 10.0 mg 6.94 Magnesium stearate (C. Erba, Milano, I) 2.0mg 1.4 Colloidal silica (Syloid 244, Grace 2.0 mg 1.4 GmbH, Worms, D)Total 144.0 mg

1-b-Composition of the second layer:

Hydroxypropylmethylcellulose 36.65 mg (Methocel E50 Premium, Colorcon,Orpington, UK) Lactose monohydrate (USP grade, C. 38.15 mg Erba, Milano,I) Glyceryl behenate (Compritol 888ATO 18.80 mg Gattefossé Saint Priest,F.) Polyvinylpyrrolidone (Plasdone K29-32 5.00 mg ISP Corp., Wayne, NY,USA) Yellow iron oxyde (Eingemann- 0.10 mg Veronelli, Milano, I.)Magnesium stearate (USP grade, C. 0.90 mg Erba, Milano, I.) Colloidalsilica (Syloid 244, Grace 0.40 mg GmbH, Worms, D) Total 100.0 mg

A quantity of granulate necessary to obtain 5,000 tablets with twolayers is prepared.

The procedure of manufacture consists in the preparation of a wetgranulate by using sigma mod. Erweka type K 5 mixer (Frankfurt a. M.,D.), and by wetting the mixture of powders with an aqueous solution ofpolyvinylpyrrolidone at 10% (w/v) in which (in the case of the granulateof the first layer) the sodium laurylsulphate has been solubilized. Thegranulate is dried in a fluid bed apparatus (Aeromatic mod. Strea) andthen added up by lubricants.

1-c-Preparation of systems with two layers (by compression).

The obtained granulates, like previously reported and according schemeswell known by all the experts of the field, are carried out on the twocharging hoppers of a rotary compression equipment which is suitable toproduce two layer tablets (es. Elisabeth Hata). In particular in thefirst one the described granulate at 1-b point is carried; while in thesecond charging hopper the previously described granulate at 1-a pointis carried.

The compression equipment, equipped with punches of 7.0 mm of diameter,is regulated in order to produce systems with two layers which areformed by a first layer of 144.0 mg containing the active principle (60mg nifedipine) and by a second layer of 100 mg of barrier granulate.

1-e-Coating process of systems with two layers.

Composition of the coating:

Copolymer of the acrylic and 10.70 mg metacrylic acid (Eudragit L30 DRohm Pharma, D) Triethylcitrate (C, Erba, Milano, I) 1.60 mg Iron oxyde0.20 mg Total 12.50 mg

The film forming process is done by using a coating apparatus (a basin)for rapid coating (Manesty Accela-Cota) by spraying, through an “airless” system an aqueous dispersion at the 30% of acrylic and metacrylicacid copolymer (Eudragit L 30 D) in which the triethylacetate issolubilized.

A temperature of about 40-50° C. is used for the entrance air, accordingto the known art, obtaining tablets completely covered by a uniformcoating film of the previously reported polymeric materials.

EXAMPLE 2

Preparation of a series of (5,000) tablets containing Nifedipine 60 mgas active principle.

A two layers tablet is prepared with a composition exactly identical tothat reported in the example 1 with only the substitution in the firstlayer formulation of the hydroxypropylmethylcellulose (Methocel K 100M,) 20.0 mg with an identical quantity of hydroxypropylmethylcellulose(Methocel K 15 M). The second layer maintains identical composition.

EXAMPLE 3

Preparation of a series of (5,000) tablets containing Nifedipine 60 mgas active principle.

A two layers tablet is prepared with a composition exactly identical tothat reported in the example 1 with only the substitution in the firstlayer formulation of the hydroxypropylmethylcellulose (Methocel K 100M,) 20.0 mg with an identical quantity of hydroxypropylmethylcellulose(Methocel K 4 M). The second layer maintains identical composition.

f-Dissolution test

Example no 1, example no 2, example no 3:

In order to estimate the characteristics of the active principle releaseby the prepared and described systems in the example 1, 2, and 3, theapparatus 2 is used, paddle(USP XXII) by working at 100 r.p.m. and usingas dissolution fluid 1 l of buffer solution at pH 6.8 formed bytris-hydroxy-methylaminomethane 0.1M, which contains 1% of polysorbate80. The release of the active principle is followed through thespectrophotometric UV determination by using an automatic system ofsampling and reading (Beckman).

The results of the trials are reported in table 1.

TABLE 1 % released % released % released Time (h) Example n°1 Examplen°2 Example n°3 1  3.8  8.1  8.1 2  9.2 24.6 25.0 3 15.4 47.7 62.7 425.8 79.2 91.5 5 42.3 96.1 97.3 6 53.5 98.5 99.7 8 81.5 99.1 101.0  10 97.3

From the analysis of table 1, it's evident that the utilization ofhydroxypropylmethylcellulose of different molecular weight deeplymodifies the release speed of the active principle. In particular in theexample 1 hydroxypropylmethylcellulose is used at high molecular weight(Methocel K 100 M,) in the example 2 hydroxypropylmethylcellulose isemployed at medium molecular weight (Methocel K 15 M) and in the example3 at low molecular weight (Methocel K 4M) (see FIG. 1, too).

“In vivo” trials

In order to estimate the characteristics of bioavailability of theactive principle carried out in the pharmaceutical formulation describedin the example 1, a “cross over” experiment has been done with 12healthy volunteers by using the medical speciality Procardia XL, asreference formulation, containing the same quantity of nifedipine.

In particular the following parameters has been determined:

C_(max)=maximum haematic concentration (peak) in ng/ml

T_(max)=time to achieve the peak

AUC(o-inf)=area under curve from 0 to infinity

The results are expressed as percentage in respect to the referenceformulation.

C_(max=)91.0%

T_(max=)73.3%

AUC (o-inf)=90.9%

From the “in vivo” reported data, the pharmaceutical formulationdescribed in the example 1 results bioequivalent in respect to thereference formulation, being AUC clearly over the 80%.

EXAMPLE 4

Preparation of a series of (5,000) tablets containing Nifedipine 60 mgas active principle.

A two layer tablet is prepared with a composition exactly identical tothat reported in the example 1 with the only substitution in the firstlayer formulation of the quantity of sodium laurylsulphate used: insteadof 10.0 mg 15.0 mg are employed. The method of production is the sametoo. The second layer maintains identical composition.

EXAMPLE 5

Preparation of a series of (5,000) tablets containing Nifedipine 60 mgas active principle.

A two layer tablet is prepared with a composition exactly identical tothat reported in the example 1 with the only substitution in the firstlayer formulation of the quantity of sodium laurylsulphate used: insteadof 10.0 mg, 20.0 mg are employed. The method of production is the sametoo. The second layer maintains identical composition.

EXAMPLE 6

Preparation of a series of (5,000) tablets containing Nifedipine 60 mgas active principle.

A two layer tablet is prepared with a composition exactly identical tothat reported in the example 1 with the only substitution in the firstlayer formulation of the quantity of sodium laurylsulphate used: insteadof 10.0 mg, 30.0 mg are employed. The method of production is the sametoo. The second layer maintains identical composition.

Dissolution test

Example no 4, Example no 5, Example no 6

In order to estimate the characteristic of the active agent release bythe prepared and described systems in the example 4, 5, and 6, theapparatus 2 is used, paddle(USP XXII) by working at 100 r.p.m. and usingas dissolution fluid 1 l of buffer solution at pH 6.8 composed bytris-hydroxy-methylaminomethane 0.1M, which contains 1% of polysorbate80. The release of the active agent is followed through thespettrophotometric UV determination by using a automatic system ofsampling and reading (Beckman).

The results of the trials are reported in table 2.

TABLE 2 % release % release % release Time (h) Example n°4 Example n°5Example n°6 1  6.6  6.8 16.9 2 12.9 15.4 50.8 3 23.1 43.1 83.8 4 41.571.9 96.2 5 61.5 90.7 99.6 6 79.2 99.5 7 88.5 8 96.2 9 99.2 10  100.3 

From the analysis of table 2 it appears evident that the employment ofgrowing quantities of sodium laurylsulphate in the preparationdetermines a great increase of the of release speed of the activeprinciple from the pharmaceutical formulation (see FIG. 2, too).

EXAMPLE 7

Preparation of a series of (5,000) tablets containing Nifedipine 60 mgas active principle.

7-a-Composition of the first layer:

% weight Nifedipine (0.5 m²/g) 60.0 mg 41.66 Lactose monohydrate (USPgrade) 30.0 mg 20.83 Hydroxypropylmethylcellulose 30.0 mg 20.83(Methocel K100 M, Colorcon, Orpington, UK) Polyvinylpyrrolidone(Plasdone K29- 10.0 mg 6.94 32, I.S.P., Wayne, NY, USA) Polyaxyethylenglycol 10.0 mg 6.94 (Gattefossé Saint Priest, F) Magnesium stearate (C.Erba, 2.0 mg 1.4 Milano, I) Colloidal silica (Syloid 244, Grace 2.0 mg1.4 GmbH, Worms, D) Total 144.0 mg

7-b-Composition of the second layer:

% weight Hydroxypropylmethylcellulose 26.77 mg 38.34 (Methocel E50Premium, Colorcon, Orpington, UK) Lactose monohydrate (USP grade, C.26.77 mg 38.34 Erba, Milano, I) Glyceryl behenate (Compritol 12.89 mg18.41 888ATO Gattefosse Saint Priest, F.) Polyvinylpyrrolidone (PlasdoneK29- 2.45 mg 3.5 32 ISP Corp., Wayne, NY, USA) Yellow iron oxyde(Eingemann- 0.07 mg 0.1 Veronelli, Milano, I.) Magnesium stearate (USPgrade, C. 0.70 mg 1 Erba, Milano, I.) Colloidal silica(Syloid 244, Grace0.35 mg 0.5 GmbH, Worms, D) Total 70.0 mg

A quantity of granulate necessary to obtaining 5,000 tablets with twolayers is prepared.

The procedure of manufacture consists in the preparation of a wetgranulate by using sigma mod. Erweka type K 5 mixer (Frankfurt a. M.,D.), and by wetting the mixture of powders with an aqueous solutions ofpolyvinylpyrrolidone at 10% (w/v) in which (in the case of the granulateof the first layer) the polyoxyethylenglycol has been solubilized. Thegranulate is dried in a fluid bed apparatus (Aeromatic mod. Strea) andthen added up by lubricants.

7-c-Preparation of systems with two layers (by compression).

The obtained granulates, like previously reported and like schemes wellknown by all the experts of the field, are carried out on the twocharging hoppers of a rotary compression equipment which is suitable toproduce two layers tablets (es. Elisabeth Hata). In particular in thefirst one the described granulate at 7-b point is carried; while in thesecond charging hopper the previously described granulate at 7-a pointis carried.

The compression-equipment, equipped with punches of 7.0 mm of diameter,is regulated in order to produce systems with two layers which areformed by a first layer of 144.0 mg including the active principle (like60 mg nifedipine) and by a second layer of 70 mg of barrier granulate.

EXAMPLE 7

Dissolution test.

In order to estimate the characteristic of active principle release bythe prepared and described system in the example 7, the apparatus 2 isused, paddle(USP XXII) by working a 100 r.p.m. and using as dissolutionfluid 1 l of distilled water, which contains 1% of polysorbate 80. Theactive principle release is followed through the spectrophotometric UVdetermination by using an automatic system of sampling and reading(Beckman).

The results of the trials are reported in table 3

TABLE 3 % released Time (h) Example n°7  1  2.2  2  5.0  4 12.0  6 21.4 8 31.2 10 40.4 12 49.5 16 67.4 20 84.6 24 98.8

“In vivo” trials

In order to estimate the characteristics of bioavailability of theactive principle carried in the pharmaceutical formulation described inthe example 7, a “cross over” experiment has been done with 12 healthyvolunteers by using the medical speciality Procardia XL, as referenceformulation, containing the same quantity of nifedipine.

In particular the following parameters has been determined:

C_(max) and AUC

The results are referred as percentage compared to the referenceformulation:

C_(max=)123.3%

AUC (0-inf)=90.8%

From the “in vivo” reported data, the pharmaceutical formulationdescribed in the example 7 results bioequivalent in respect to thereference formulation, being AUC clearly over the 80%.

What is claimed is:
 1. A pharmaceutical tablet for oral administration,able to release under controlled speed, nifedipine, said tablet,consisting essentially of at least one first layer obtained bycompression of a mixture of ingredients in the form of a powder orgranulate, said first layer comprising 9% to 80% by weight of nifedipinebased on the total weight of said first layer, said first layer furthercomprising sodium lauryl sulfate at a ratio of 6:1 by weight of thenifedipine and 3% to 90% of hydroxypropylmethylcellulose having aviscosity of 100,000 cps; one or more barrier layers which comprise from5% to 90% of a component selected from the group consisting ofpharmaceutically acceptable and biocompatible polymeric substances,based on the total weight of said barrier layer or layers having eitherthe properties to swell or to form gels or slowly erode in contact withwater or aqueous fluids and which control the release of the activeprinciple, and a coating layer which completely covers said at least onefirst layer and said barrier layer, said coating layer comprising acopolymer which comprises acrylic and methacrylic acid.
 2. Apharmaceutical tablet for oral administration, able to release undercontrolled speed, an active principle, having a water solubility at 20°C. which is lower than 50 mg/ml, said tablet consisting essentially ofat least one first layer obtained by compression of a mixture ofingredients in the form of a powder or granulate, said first layercomprising 9% to 80% by weight of the active principle, based on thetotal weight of said first layer, said first layer further comprisingsodium lauryl sulfate at a ratio of 6:1 by weight of the activeprinciple and 3% to 90% of hydroxypropylmethylcellulose having aviscosity of 100,000 cps; one or more barrier layers which comprise from5% to 90% of a component selected from the group consisting ofpharmaceutically acceptable and biocompatible polymeric substances,based on the total weight of said barrier layer or layers having eitherthe properties to swell or to form gels or slowly erode in contact withwater or aqueous fluids and which control the release of the activeprinciple, and a coating layer which completely covers at least onefirst layer and said barrier layer, said coating layer comprising acopolymer which comprises acrylic and methacrylic acid.
 3. Thepharmaceutical tablet of claim 2, wherein the active principle isselected from the group consisting of nifedipine, nicardipine,nitrendipine, nimodipine, niludipine, nilvadipine, nisoldipine,fenofibrate, nafiazone, and terfenadine.
 4. A pharmaceutical tablet fororal administration, able to release under controlled speed, an activeprinciple selected from the group consisting of nifedipine, nicardipine,nitrendipine, nimodipine, niludipine, nilvadipine, nisoldipine,fenofibrate, naftazone, and terfenadine, said tablet consistingessentially of at least one first layer obtained by compression of amixture of ingredients in the form of a powder or granulate, said firstlayer comprising 9% to 80% by weight of the active principle based onthe total weight of said first layer, said first layer furthercomprising sodium lauryl sulfate at a ratio of 6:1 by weight of theactive principle and 3% to 90% of hydroxypropylmethylcellulose having aviscosity of 100,000 cps; one or more barrier layers which comprise from5% to 90% of a component selected from the group consisting ofpharmaceutically acceptable and biocompatible polymeric substances,based on the total weight of said barrier layer or layers having eitherthe properties to swell or to form gels or slowly erode in contact withwater or aqueous fluids and which control the release of the activeprinciple, and a coating layer which completely covers at least onefirst layer and said barrier layer, said coating layer comprising acopolymer which comprises acrylic and methacrylic acid.